Alzheimer's disease is a degenerative disorder of the human brain. Clinically, it appears as a progressive dementia. Its histopathology is characterized by degeneration of neurons, gliosis, and the abnormal deposition of proteins in the brain. Proteinaceous deposits (called "amyloid") appear as neurofibrillary tangles, amyloid plaque cores, and amyloid of the congophilic angiopathy. [For a review, see, D. J. Selkoe, Neuron, 6:487-498 (1991)]
While there is no general agreement as to the chemical nature of neurofibrillary tangles, the major constituent of both the amyloid plaque cores and the amyloid of the congophilic angiopathy has been shown to be a 4500 Dalton protein originally termed .beta.-protein or amyloid A4. Throughout this document this protein is referred to as .beta.-amyloid peptide or protein.
.beta.-amyloid peptide is proteolytically derived from a transmembrane protein, the amyloid precursor protein. Different splice forms of the amyloid precursor protein are encoded by a widely expressed gene. see, e.g., K. Beyreuther and B. Muller-Hill, Annual Reviews in Biochemistry, 58:287-307 (1989). .beta.-amyloid peptide consists, in its longest forms, of 42 or 43 amino acid residues. J. Kang, et al., Nature (London), 325:733-736 (1987). These peptides, however, vary as to their amino-termini. C. Hilbich, et al., Journal of Molecular Biology, 218:149-163 (1991).
Because senile plaques are invariably surrounded by dystrophic neurites, it was proposed early that .beta.-amyloid peptide is involved in the loss of neuronal cells that occurs in Alzheimer's disease. B. Yankner and co-workers were the first to demonstrate that synthetic .beta.-amyloid peptide could be neurotoxic in vitro and in vivo. B. A. Yankner, et al., Science, 245:417 (1989); See, also, N. W. Kowall, et al., Proceedings of the National Academy of Sciences, U.S.A., 88:7247 (1991). Other research groups, however, were unable to consistently demonstrate direct toxicity with .beta.-amyloid peptide. See, e.g., Neurobiology of Aging, 13:535 (K. Kosik and P. Coleman, eds. 1992). Even groups receiving .beta.-amyloid peptide from a common source demonstrate conflicting results. P. May, et al., Neurobiology of Aging, 13:605-607 (1992).
In addition to Alzheimer's disease, Down's syndrome is also characterized by an accumulation of .beta.-amyloid peptide. In patients suffering from Down's syndrome the .beta.-amyloid peptide is the primary constituent of senile plaques and cerebrovascular deposits.
Because of the debilitating effects of Alzheimer's disease, Down's syndrome, and these other conditions associated with amyloidogenic peptides and proteins there continues to exist a need for effective treatments. This invention provides compounds efficacious in the treatment and prevention of these disorders.